Depression, dementia, and slowing of intellectual function affect nearly half of the population over the age of 65. Investigation of degenerative diseases of the nervous system that cause these behaviors is crucial for understanding their pathogenesis and for developing rational strategies for treatment. Parkinson's disease is a common degenerative disorder of the aging nervous system that is usually conceptualized as a disorder of movement. However, it is now recognized that Parkinsonian patients develop intellectual difficulty and depressive disorders at a much greater rate than expected. Neurotransmitter alterations in Parkinson's disease include not only dopamine but also serotonin and norepinephrine. Investigation of behavioral relationships to these neurotransmitter systems could serve as a model for the study of similar problems in the aged. We intend to test two hypotheses developed from our previous investigations. First, that depression is a syndrome associated with a disorder of serotonin metabolism in Parkinson's disease, and second, that slowing of intellectual function, termed bradyphrenia, is a disorder related to a disturbance in norepinephrine metabolism. We plan to examine a large number of patients and an equal number of controls to confirm the relationships between serotonin and depression by measuring various components of serotonin metabolism, conducting a clinical trial of the serotonin precursor (5-hydroxytryptophan) in depressed Parkinsonians, and monitoring the prevalence of depressive symptoms in Parkinsonians with a reduction in the metabolite of serotonin in cerebrospinal fluid. To further examine our second hypothesis, we intend to re-explore the relationship of bradyphrenia to norepinephrine metabolism in both cerebrospinal fluid and plasma. We also intend to conduct clinical trials of two norepinephrine agonists in Parkinsonians in order to explore the role of catecholamines in intellectual function. This investigation has direct application to Parkinson's disease, but more importantly, it will broaden our understanding of the relationships between behavioral changes and biochemical alterations in diseases of the aging nervous system.